Cancer causes about 13% of all human deaths and the success of treatment is in many cases linked to the stage at which the cancer is diagnosed. There is therefore a need for better diagnostic and risk prediction (prognostic) tools for patients suffering from all types of cancer.
Chemokines play an important role inter alia in immune and inflammatory responses in various diseases, including cancer, viral infections, asthma and allergic diseases, as well as autoimmune pathologies such as rheumatoid arthritis and atherosclerosis. These small, secreted molecules are a growing superfamily of 8-14 kDa proteins characterised by a conserved four cysteine motif. The actions of chemokines are mediated by subfamilies of G protein-coupled receptors. Chemokines are divided into four different groups, CXC, CC, CX3C or C, depending on the position of the conserved cysteine residue, and receptor nomenclature essentially follows that of the chemokines. Thus, CC chemokines bind to CC chemokine receptors, CXC ligands bind to CXC receptors and so on.
Chemokine receptors and their ligands direct the trafficking of cells in normal tissue homeostasis and in disease, influencing cell motility, invasiveness and survival. In cancer, certain chemokines and their receptors are important for cell trafficking into and out of the tumour microenvironment. For instance, chemokines made by malignant and stromal cells can contribute to the extent and phenotype of the tumour-associated leukocyte component, to angiogenesis and to the generation of the fibroblast stroma. These stromal chemokines may also directly aid survival of the malignant cells. This is because malignant cells gain functional chemokine receptors that are not normally found on their normal counterparts. These receptors may contribute to metastatic activity; malignant cells become like leukocytes, able to respond to chemokine gradients at sites of metastasis.
Chemokine thymus and activation-regulated chemokine (TARC), also known as CCL17, displays chemotactic activity for T-lymphocytes, but not monocytes or granulocytes. It can specifically bind to chemokine receptor CCR4. In normal tissues, CCL17 is expressed by vascular and lymphatic endothelial cells, but is also produced by macrophages, dendritic cells and keratinocytes.
Macrophage-derived chemokine (MDC), also known as CCL22, can also specifically bind to chemokine receptor CCR4. CCL22 is generally considered to be a constitutively expressed chemokine, although it appears that its expression may also be modulated by certain stimuli. In normal tissues, CCL22 is a product of macrophages, monocytes, dendritic cells, B cells, and T cells. It is also found in epithelial tissues. For instance, intestinal epithelium constitutively produces CCL22 that can be further up-regulated by inflammatory cytokines such as TNF-α.
CCL17 and CCL22 are also found at increased levels at the site of tumours. Immunohistochemistry has revealed increased levels of CCL17 and CCL22 both at epithelial tumour cells and at cells that form the tumour stroma, for example in cervical cancer (WO2009037454).
Studies have demonstrated that the actions of chemokines are mediated by subfamilies of G protein-coupled receptors, among which is the receptor designated chemokine (C-C motif) receptor 4, or CC chemokine receptor 4 (CCR4). Specific ligands for CCR4 include CCL17 and CCL22.
CCR4 is believed to be important inter alia in the function of T cell chemotaxis and the migration of phagocytic cells to sites of inflammation. CCR4 is preferentially expressed on T-helper cell type 2 (Th2) cells and regulatory T (Treg) cells, whereas only limited expression on other healthy cells or tissues occurs.
CCR4 expression has also been detected in tumours. Tumours are a heterogeneous mixture of cells, being made up of inter alia neoplastic cells, fibroblasts, endothelial and immune-competent cells. Macrophages may represent up to 50% of tumour mass. Thus, tumours may include infiltrating immune cells, and these immune cells may express CCR4.
CCR4 is also expressed by certain neoplastic tumour cells. More specifically, CCR4 may be found not only in the tumour stroma, but it may expressed by epithelial tumour cells, i.e. neoplastic cells. Adult T cell leukaemia/lymphoma cells have long been known to express CCR4. More recently, CCR4 has also been found to be expressed by the neoplastic tumour cells of certain carcinomas (WO2009/037454 and WO2012/076883). CCR4 expression is believed to be an early event in carcinogenesis, particularly cancer of the cervix, oesophagus, kidney, brain, breast, ovary, prostate, stomach and pancreas. Thus, both haematological and non-haematological cancer cells, e.g. solid tumour cells, may express CCR4.
Various methods for the diagnosis, prognosis and/or monitoring of cancer exist, but there remains a need for further methods to advance the diagnosis, prognosis, monitoring and the like of cancer.